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- Title
Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme.
- Authors
Fedoryshchak, Roman O.; Přechová, Magdalena; Butler, Abbey M.; Lee, Rebecca; O'Reilly, Nicola; Flynn, Helen R.; Snijders, Ambrosius P.; Eder, Noreen; Ultanir, Sila; Mouilleron, Stephane; Treisman, Richard
- Abstract
PPP-family phosphatases such as PP1 have little intrinsic specificity. Cofactors can target PP1 to substrates or subcellular locations, but it remains unclear how they might confer sequence-specificity on PP1. The cytoskeletal regulator Phactr1 is a neuronally enriched PP1 cofactor that is controlled by G-actin. Structural analysis showed that Phactr1 binding remodels PP1's hydrophobic groove, creating a new composite surface adjacent to the catalytic site. Using phosphoproteomics, we identified mouse fibroblast and neuronal Phactr1/PP1 substrates, which include cytoskeletal components and regulators. We determined high-resolution structures of Phactr1/PP1 bound to the dephosphorylated forms of its substrates IRSp53 and spectrin aII. Inversion of the phosphate in these holoenzyme-product complexes supports the proposed PPP-family catalytic mechanism. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with the composite Phactr1/PP1 surface, which are required for efficient dephosphorylation. Sequence specificity explains why Phactr1/PP1 exhibits orders-of-magnitude enhanced reactivity towards its substrates, compared to apo-PP1 or other PP1 holoenzymes.
- Subjects
SPECTRIN; FIBROBLASTS; DEPHOSPHORYLATION; PHOSPHATASES; CYTOSKELETAL proteins; MICE
- Publication
eLife, 2020, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.61509